CORRELATES OF HIV-1 PROTECTION

HIV-1 保护的相关性

• 批准号: 6738054
• 负责人: Phyllis J. Kanki
• 金额: $ 35.54万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738054
• 关键词: AIDS /HIV test; AIDS education /prevention; Africa; HIV infections; cellular immunity; chemokine; clinical research; communicable disease transmission; cross immunity; female; human immunodeficiency virus 1; human immunodeficiency virus 2; human subject; leukocytes; prostitution; sexually transmitted diseases

Beta chemokines have now been identified as potent soluble suppressors of macrophage-tropic HIV infection, in vitro. Studies of multiply exposed uninfected individuals have implicated the role of elevated beta chemokines in HIV resistance, in many cases, independent of genetic mutations in the chemokine receptor. Macaque studies have also suggested a role for beta-chemokines in vaccine induced protective immunity using a variety of vaccine candidates and live virus challenge. The close genetic and antigenetic relationship of HIV-2 with HIV-1 and the discordant biological phenotypes, led us to hypothesize that HIV-2 might afford protection from subsequent HIV-1 challenge. We have reported 52-74% protection in HIV-2 infected women that were observed for subsequent infection with HIV-1, our observation period has now been extended to over 13 years. In our quest for identifying the mechanism of this protection, we have recently demonstrated that approximately 60% of HIV-2 infected stimulated PBMCs are resistant to HIV-1 R5 infection compared with X4 viruses. This relative resistance was transferable, CD8 dependent and strongly correlated with beta chemokine production in the media. All relatively resistant cultures were rendered susceptible by addition of antibodies to beta chemokines. Our specific aims include in vitro and in vivo studies. 1. We will further identify and characterize the HIV-2 resistant phenotype the cellular sources of beta chemokines will be studied and each beta chemokine's contribution to the relative resistance phenotype will be assessed. 2. We will determine if beta chemokine secretion is specifically induced by HIV-2 infection, and correlate beta chemokine message with the secreted chemokine message with the secreted chemokine, in vitro. - we will determine if HIV-2 envelope/CD8 interactions contribute to an HIV-2 specific induction of beta chemokines and HIV-1 relative resistance. 3. We will determine if HIV-2 infected women continue to demonstrate protection from HIV-1 infection, partial protection will be evaluated with HIV-1 viral RNA l4evels as a secondary outcome. 4. We will determine the profile of beta chemokine message and protein in the evaluated HIV-2 infected women and study the association of beta chemokines with in vivo protection from HIV-1 infection.

β趋化因子现已被鉴定为体外巨噬细胞嗜性 HIV 感染的有效可溶性抑制剂。对多次暴露的未感染个体的研究表明，β趋化因子升高在艾滋病毒抵抗中的作用，在许多情况下，与趋化因子受体的基因突变无关。猕猴研究还表明，β-趋化因子在使用多种候选疫苗和活病毒攻击的疫苗诱导的保护性免疫中发挥着作用。 HIV-2 与 HIV-1 密切的遗传和抗原关系以及不一致的生物表型使我们推测 HIV-2 可能提供保护以免受随后的 HIV-1 挑战。我们报告称，在观察到随后感染 HIV-1 的 HIV-2 感染女性中，保护率达到 52-74%，我们的观察期现已延长至 13 年以上。在我们寻求确定这种保护机制的过程中，我们最近证明，与 X4 病毒相比，大约 60% 的 HIV-2 感染刺激的 PBMC 对 HIV-1 R5 感染具有抵抗力。这种相对阻力是可转移的、CD8依赖性的并且与培养基中β趋化因子的产生密切相关。通过添加β趋化因子的抗体，所有相对抗性的培养物都变得敏感。我们的具体目标包括体外和体内研究。 1. 我们将进一步鉴定和表征 HIV-2 耐药表型，将研究 β 趋化因子的细胞来源，并评估每种 β 趋化因子对相对耐药表型的贡献。 2. 我们将确定β趋化因子分泌是否是由HIV-2感染特异性诱导的，并在体外将β趋化因子信息与分泌趋化因子信息与分泌趋化因子相关联。 - 我们将确定 HIV-2 包膜/CD8 相互作用是否有助于 HIV-2 特异性诱导 β 趋化因子和 HIV-1 相对耐药性。 3. 我们将确定 HIV-2 感染妇女是否继续表现出对 HIV-1 感染的保护，部分保护将使用 HIV-1 病毒 RNA 14 水平作为次要结果进行评估。 4. 我们将确定受评估的 HIV-2 感染女性中 β 趋化因子信息和蛋白质的概况，并研究 β 趋化因子与体内防止 HIV-1 感染的关联。